The initial interaction of ozone with lung tissue results in damage to alveolar and bronchiolar epithelia and the infiltration of polymorphonuclear leukocytes (PMNs). Preliminary studies have demonstrated that these cells have the potential to increase the generation of reactive oxygen intermediates within the lung. A possible contribution of these cells to the development of lung injury was further demonstrated by decreased ozone-induced lung permeability damage in rats made neutropenic by cyclophosphamide pretreatment. The present proposal is designed to identify the biochemical determinants of initial ozone injury, and to test the hypothesis that ozone-induced inflammatory cells contribute to the initial epithelial damage, and subsequently interfere with epithelial and extracellular matrix repair processes. The initial biochemical and cellular events associated with the first 6 hours of exposure of rats to ozone concentrations of < 1.0 ppm will be established by correlating changes in lung metabolic capabilities with infiltration of PMNs and increases in lung permeability. The biochemical and cellular determinants of initial lung cell injury will be investigated using sensitive measurements of lipid damage, enzyme inactivation, and increased permeability in lungs isolated from O3-exposed rats with altered anti- oxidant enzyme activities and tissue glutathione levels, and with increased and decreased lung PMN contents. Lung PMN content will be increased by pretreatment by intratracheal administration with a chemotactic peptide. PMN-infiltration will be diminished by pretreatment with rabbit anti-sera against rat PMNs. Measurements of lavage cell superoxide-anion generation and luminol-amplified chemiluminescence will be used to establish the potential of infiltrating inflammatory cells to contribute to O3-induced lung damage. The consequences of altered anti-oxidant defenses, PMN infiltration, and continued ozone exposure on epithelial and extracellular matrix repair processes will be evaluated in lungs isolated from rats exposed for 6 hours a day to 0.5 ppm ozone for up to 14 days. Measurements of cell turnover and extracellular matrix protein synthesis will be correlated with changes in lung intermediary metabolism and with specific cell metabolic functions. These studies are designed to increase our understanding of the mechanisms of ozone-induced lung injury and identify how differences in inflammatory cell infiltration and in anti-oxidant defenses might account for differences in susceptibility to the damaging effects of ozone exposure observed in humans.